Mechanisms of serotonin regulating food intake: the role of the melanocortin pathway

Lora Heisler & Daniel Lam

The central serotonin (5-hydroxytryptamine, 5-HT) system is an established modulator of energy balance. Therefore, it is unsurprising that former (e.g. D-fenfluramine), current (e.g. sibutramine), and drug discovery (e.g. lorcaserin) obesity treatments target serotonin pathways to affect food intake and body weight. Pharmacological and genetic research implicates the Gq-coupled serotonin 2C receptor (5-HT2CR) and the Gi-coupled serotonin 1B receptor (5-HT1BR) specifically in these effects. We sought to clarify how serotonin in general, and the 5-HT2CRs and 5-HT1BRs in particular, modulate ingestive behavior. Through a combination of functional neuroanatomy, genetic, feeding, and electrophysiology studies in rodents, we found that 5-HT2CR and 5-HT1BR agonists require melanocortin pathways to exert their effects on appetite. Specifically, we observed that serotonin and 5-HT2CR agonists activate neurons expressing the endogenous anorectic melanocortin agonist proopiomelanocortin (POMC)/α-melanocyte stimulating hormone (α-MSH) and that serotonin and 5-HT1BR agonists inhibit the activity of neurons expressing the endogenous orexigenic melanocortin antagonist agouti-related peptide (AgRP) in the arcuate nucleus of the hypothalamus. We further verified the necessity for 5-HT2CRs expressed on POMC neurons in serotonins effects on energy balance using a genetic mouse line in which 5-HT2CRs are exclusively expressed in POMC neurons. Exclusive expression of 5-HT2CR on POMC neurons abolished the hyperphagia, obesity, and attenuated anorectic responses to serotonergic drugs evident in the complete 5-HT2CR knockout, illustrating that 5-HT2CRs specifically on POMC neurons underlie the effects of 5-HT2CR agonists on energy balance. In the brain, α-MSH and AgRP compete for action at the melanocortin 3 (MC3) and melanocortin 4 (MC4) receptors. To further clarify the pathway through which serotonin influences appetite, we examined whether pharmacological blockade or genetic inactivation of the MC3Rs or MC4Rs abolishes D-fenfluramine, 5-HT2CR and/or 5-HT1BR agonist hypophagia. We observed that activation of the MC4Rs, but not the MC3Rs, is required for D-fenfluramine, 5-HT2CR and 5-HT1BR agonists to influence feeding. A model is presented in which activation of the melanocortin system is downstream of serotonin and is necessary to produce the complete anorectic effect of serotonergic compounds.